Thursday, November 14, 2013
1:00 pm
Warren and Katharine Schlinger Laboratory

Special Chemical Engineering Seminar

Ultrasound-induced blood-brain barrier opening and drug delivery
Mania Samiotaki, PhD candidate, Columbia University

                   Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, remains a unique technique that can induce localized BBB opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The objective in this presentation is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption, and the delivery of agents to the brain parenchyma thereafter. The BBB opening in vivo is monitored through passive cavitation detection (PCD) during treatment, while Magnetic Resonance Imaging (MRI) in both mice and non-human primates are used to assess BBB opening's characteristics such as the permeability, the volume of opening and the reversibility timeline. The safety of BBB disruption is assessed upon histological examination of H&E stained sections. It will be shown that the BBB can be disrupted safely and transiently under specific acoustic (peak negative pressures under 0.45 MPa) and microbubble (diameter under 8 µm) conditions. The permeability of the BBB has been measured to increase by at least two orders of magnitude while closing is highly dependent on the pressure amplitude, pulse length and microbubble diameter used and can vary between 3 hours and 5 days. Finally, delivery of different molecular weights and constituency including therapeutic compounds, such as neurotrophic factors such as BDNF, NTN and AAV-NTN,  through the opened BBB after intravenous injection will be shown with specific examples and evidence of neuronal uptake, efficient bioavailability and downstream signaling to the neuronal nuclei. 

Benefits:

• Noninvasive and targeted approaches to transient opening of the blood-brain barrier

• Drugs currently shelved could be used in conjunction with this technique

• Neurotrophic factors have been shown to be successfully delivered

• Feasibility in large animals demonstrated

Seminar will be in 118 Schlinger (ground floor conference room)

 

 

Contact Martha Hepworth martha@cheme.caltech.edu
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